The objective of the proposed research is to explore a new clinically applicable approach for safe bone marrow (BM) and organ transplantation. We have recently demonstrated that permanent survival of BM and organ allografts can be accomplished across major histocompatibility (TILI) consisting of 17 daily fractions of 200 rads. BM recipients showed no signs of graft-versus-host disease (GVHD) and acquired permanent specific tolerance to donor-type skin and heart allografts. Our goal is to extend these studies and adapt a similar approach for transplantation of mismatched BM and kidney allografts in unrelated dogs and primates. Our recent pilot study in 2 dogs and 1 rhesus monkey suggests that permanent BM and organ allograft survival without GVHD can be achieved in large, randomly bred animals using TLI. The proposed research includes the following series of preclinical studies: 1) unrelated mismatched BM transplantation in normal and marrow deficient animals, using an experimental model of aplastic anemia, 2) kidney transplantation followng TILI alone or with infusion of donor BM cells for tolerance induction, 3) therapy of established GVHD, a major obstacle in clinical BM transplantation, using TILI for selective immunosuppression, avoiding major systemic marrow toxicity, 4) Adoptive immunotherapeutic effects of mismatched marrow allografts following TILI in conjunction with chemo-radiotherapy as a possible approach for the treatment of disseminated neoplastic disorders, using a murine B cell leukemia as an experimental model. In summary, TILI might provide a new multipurpose clincial tool for BM and organ transplantation avoiding GVHD, despite histoincompatibility between the donor and the recipient, since similar techniques to those described are routinely and safely used to treat human lymphoid malignancies.